The left ventricle (LV) can augment its performance during chronic volume overload with no further use of the Frank-Starling mechanisms, and hypertrophy is the primary adaptive mechanism to maintain wall stress within a certain limit. These findings are supported by serial studies with left ventriculography that revealed progressive dilation of the LV chamber and a moderate increase in the LV wall thickness during chronic volume overload in the canine model. The mean velocity of the circumferential shortening showed no appreciable change, and the wall stress was elevated markedly in the early stage but gradually decreased with the development of hypertrophy. Serial studies in the canine model also indicated that hypertrophy does not necessarily result in depressed contractility.

In the clinical setting, it was shown that the moderately hypertrophied ventricle exhibits hyperfunction as a pump, but does not have intrinsic depression of cardiac contractility, while the contractility of the ventricle with advanced hypertrophy was substantially decreased.

The sequence of events during the development of hypertrophy comprises three stages. Stage one is myocardial damage and impairment of contractility; two, stable hyperfunction, in which normal myocardial function is restored; three, gradual deterioration of myocardial function leading to overt heart failure.

The importance of understanding inciting events rather than the terminal results is supported by the findings from studies with this experimental rat model, as the changes en route to heart failure occurred in a compensatory manner as early as 11 weeks. The initial event is the influx of calcium into the myocytes through the sarcolemmal calcium channels, triggering the release of the activator calcium from the local pool. In the failing stage, there was a definite ventricular dysfunction with a reduced peak level of tension development with a marked delay in the tension decay. These changes were associated with corresponding changes in the calcium transient. Impaired contractile response to beta adrenergic stimulation in the failing heart was primarily assigned to a decreased number of beta receptors and an increase in inhibitory G1 protein in the failing heart compared to the control animals; changes that occurred in the compensatory stage.

Elevated circulating levels of cytokines have been noted in patients with chronic heart failure. A growing body of evidence shows that a major subset of heart disease may be expressed via nonlethal alteration in myocyte function induced by immune cells and their cytokines. Data from Sasayama and colleagues show that plasma TNF-alpha levels are elevated in a large percentage of patients with acute myocarditis and dilated and hypertrophic cardiomyopathies, and that in patients with dilated cardiomyopathy cytokines such as IL-beta, IL-2, interferon gamma, and TNF-alpha were significantly upregulated.

Serum and myocardial concentrations of endothelin-1 (ET-1) were markedly increased four-fold and five-fold, respectively, during the transition from compensated hypertrophy to heart failure in the pressure overload hypertrophic model (Figure 4). Thus, myocardial synthesis of ET-1 was considered to play a significant role in the transition from compensated hypertrophy to heart failure. Local synthesis of ET-1 was found to be mediated by acetylated conversion from big ET-1 to ET-1 in the rat cardiac myocyte.

Endothelin converting enzyme (ECE-1) mRNA was not affected in compensated hypertrophy, but was significantly upregulated in the failing heart. ECE-1 was therefore considered to play a significant role in increasing the conversion from big ET-1 to ET-1 during the development of heart failure. Experiments of the transcriptional activity of ET-1 promoter in the upregulated expression of ET-1 in the myocardial cells showed that mutation of the GATA motif in the ET-1 promoter reduced the basal transcriptional activity by half and completely abolished the phenylephrine-mediated increase in transcription. Thus, GATA was considered essential for full transcriptional activity of ET-1. GATA-5 was shown to have the strongest transactivation ability for the ET-1 promoter (Figure 5), and its expression was markedly elevated in the failing heart. GATA-5 was thus considered to importantly relate to intranuclear signal transduction of ET-1 expression in the myocardial cells and the development of heart failure.

A significant improvement in survival was seen in the compensated hypertrophic rat with an ET receptor antagonist (bosentan) and with an ACE inhibitor (temocapril), compared to complete mortality of the entire control group by 19 weeks. Bosentan and temocapril significantly improved the functional and hemodynamic parameters, but bosentan, in contrast to temocapril, did not affect ventricular mass (Figure 6). The beneficial effects the ET receptor antagonist was considered to be mediated exclusively by improvement of ventricular dysfunction, while the effect of the ACE inhibitor was related to the improvement in remodeling.